Elevated serum Apolipoprotein B (ApoB) may represent a unifying risk factor underlying many of the world's most prevalent metabolic diseases. ApoB levels independently predict incidence of diabetes, metabolic syndrome, and cardiovascular disease even after adjusting for confounding variables. While it may seem implausible that a single disease marker could be implicated in such a broad range of diseases, the frequent clustering of these metabolic abnormalities is suggestive of shared causal risk factors. Also, the characterized roles of ApoB in lipid transport, endoplasmic reticulum stress, inflammation, and atherogenesis provide straightforward mechanistic connections to the etiologies of each linked metabolic disease. ApoB therefore represents a highly promising therapeutic target to combat the growing global burden of metabolic disease. Methods identifying agents that modulate the expression of ApoB must be developed to produce new pharmaceutical agents that prevent and/or treat these diseases.